Recent findings in both human and animal studies indicate that the severely osteopenic skeleton fails to respond adequately to bone anabolic agents such as NaF and PTH, probably due to lack of adequate numbers of bone spicules that serve as a template for new bone formation. The proposed research will focus on preclinical testing of sequential treatment with bFGF and PTH to reverse severe cancellous osteopenia in aged, ovariectomized (OVX) rats. The initial treatment with bFGF will create new bone spicules within the bone marrow whereas subsequent PTH treatment will enlarge these spicules, improve trabecular microarchitecture, and enhance bone strength. In the first experiment, the optimal dose and minimum duration of treatment with bFGF for creation of new bone spicules within the marrow cavity will be determined. In the second experiment, aged OVX rats with severe tibial cancellous osteopenia will be subjected to short-term treatment with bFGF followed by a longer period of treatment with PTH. The third experiment will determine whether prior or concurrent treatment with anti-resorptive agents will affect the skeletal response to sequential treatment with bFGF and PTH. The skeletal effects of the various treatments will be studied in cancellous bone tissue of the severely osteopenic proximal tibial metaphysis and the moderately osteopenic lumbar vertebral body and femoral neck by standard bone histomorphometric and biomechanical techniques. It is hypothesized that 1) short-term treatment with bFGF followed by a longer period of treatment with PTH will restore lost cancellous bone completely at a skeletal site with severe osteopenia, and 2) prior or concurrent treatment with the anti-resorptive agents estrogen and risedronate will not blunt the skeletal response to sequential treatment with bFGF and PTH. This is an important issue to address since patients with severe osteopenia are likely to be treated with anti-resorptive agents prior to or during bone anabolic therapy. Validation of these hypotheses would provide support for a new therapeutic strategy for treatment of osteoporotic patients with severe osteopenia who respond poorly to conventional osteoporosis therapies.